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Venetoclax resistance in preclinical KMT2A-rearranged acute lymphoblastic leukemia models is characterized by high
Anna Richter1, Lea Kinsky2, Sandra Lange2
1Department of Internal Medicine, Clinic for Hematology, Hemostasis, Oncology, Stem Cell Therapy and Palliative Medicine, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. anna.richter@med.uni-rostock.de.
Abstract:
The BCL-2 inhibitor venetoclax (VEN) has emerged as an important therapeutic backbone for hematological malignancies, but secondary resistance is a major challenge. In acute lymphoblastic leukemia (ALL), early clinical trials promise high efficacy as well. However, relapse is observed frequently, and so far, only a few resistance-inducing mechanisms have been discussed. We employed KMT2A-rearranged ALL cell lines and xenograft models to elucidate mechanisms of VEN resistance. Targeted DNA and mRNA sequencing, single-cell mRNAseq, as well as protein expression analyses were conducted. All models initially responded well but finally displayed secondary resistance. Novel as well as previously known pathogenic variants in tumor suppressor TP53 as well as pro-apoptotic molecule BAX, but not BCL2, were observed. Gene and protein expression studies demonstrated multifarious changes in resistant cells, with high inter- and intra-model heterogeneity. Finally, single-cell RNA sequencing revealed a likely contribution of the tumor microenvironment in the development of VEN resistance, as indicated by modulation of genes involved in cell-cell interaction and humoral signaling in resistance-specific clusters. Our data demonstrate and characterize the rise of VEN resistance in KMT2A-rearranged ALL models, suggesting that relapse must be expected in the clinical setting and that multifactorial processes are involved in this process.
Insights
Venetoclax resistance in KMT2A-rearranged acute lymphoblastic leukemia (ALL) involves new TP53 and BAX variants and tumor microenvironment interactions. Understanding these mechanisms is crucial for overcoming treatment relapse in ALL patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Venetoclax (VEN) is a key therapy for hematological malignancies, including acute lymphoblastic leukemia (ALL).
- Secondary resistance to VEN limits its long-term efficacy, with few mechanisms fully understood in KMT2A-rearranged ALL.
- Relapse is common in ALL treated with VEN, necessitating research into resistance pathways.
Purpose of the Study:
- To investigate the mechanisms of secondary venetoclax resistance in KMT2A-rearranged ALL.
- To characterize genetic and molecular alterations associated with VEN resistance.
- To explore the role of the tumor microenvironment in VEN resistance development.
Main Methods:
- Utilized KMT2A-rearranged ALL cell lines and xenograft models.
- Performed targeted DNA and mRNA sequencing, single-cell mRNA sequencing, and protein expression analysis.
- Analyzed gene and protein expression changes in VEN-resistant models.
Main Results:
- All models developed secondary VEN resistance after initial response.
- Identified novel and known pathogenic variants in TP53 and BAX, but not BCL2.
- Observed significant inter- and intra-model heterogeneity in gene and protein expression.
- Single-cell RNA sequencing indicated tumor microenvironment involvement via altered cell-cell interaction and signaling pathways.
Conclusions:
- Secondary VEN resistance in KMT2A-rearranged ALL is multifactorial, involving genetic alterations and the tumor microenvironment.
- Relapse due to VEN resistance should be anticipated in clinical settings.
- Further research into these mechanisms is essential for improving ALL treatment outcomes.
